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United States Patent |
6,140,479
|
Asaka
,   et al.
|
October 31, 2000
|
Erythromycin a derivatives
Abstract
An erythromycin A derivative represented by Formula (I):
##STR1##
wherein R is a pyridyl group, a quinolyl group, a nitrophenyl group or a
methoxyphenyl group, or a pharmaceutically acceptable salt thereof has a
strong antibacterial activity not only against erythromycin-sensitive
bacteria but also against certain erythromycin-resistant bacteria and
Haemophilus influenzae.
Inventors:
|
Asaka; Toshifumi (Tokyo, JP);
Ishii; Takaaki (Tokyo, JP);
Tanikawa; Tetsuya (Tokyo, JP);
Kashimura; Masato (Tokyo, JP)
|
Assignee:
|
Taisho Pharmaceuticals Co., Ltd. (JP)
|
Appl. No.:
|
381507 |
Filed:
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September 21, 1999 |
PCT Filed:
|
March 23, 1998
|
PCT NO:
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PCT/JP98/01240
|
371 Date:
|
September 21, 1999
|
102(e) Date:
|
September 21, 1999
|
PCT PUB.NO.:
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WO98/42720 |
PCT PUB. Date:
|
October 1, 1998 |
Foreign Application Priority Data
Current U.S. Class: |
536/7.2; 514/29; 536/7.4 |
Intern'l Class: |
C07H 017/08; A61K 031/70 |
Field of Search: |
536/7.2,7.4
514/29
574/29
|
References Cited
U.S. Patent Documents
3923784 | Dec., 1975 | Kierstead et al. | 560/210.
|
4331803 | May., 1982 | Watanabe et al. | 536/7.
|
4742049 | May., 1988 | Baker et al. | 514/29.
|
5631354 | May., 1997 | Asaka et al. | 536/7.
|
5656607 | Aug., 1997 | Agouridas et al. | 514/29.
|
5770579 | Jun., 1998 | Agouridas et al. | 514/29.
|
Foreign Patent Documents |
487411 | Nov., 1991 | EP.
| |
619320 | Dec., 1992 | EP.
| |
638584 | Apr., 1993 | EP.
| |
676409 | Apr., 1995 | EP.
| |
62-292795 | Dec., 1987 | JP.
| |
7278177 | Oct., 1995 | JP.
| |
Primary Examiner: Minnifield; Nita
Assistant Examiner: Baskar; Padma
Attorney, Agent or Firm: Lorusso & Loud
Claims
What is claimed is:
1. An erythromycin A derivative represented by Formula (I):
##STR4##
wherein R is a pyridyl group, a quinolyl group, a nitrophenyl group or a
methoxyphenyl group; or a pharmaceutically acceptable salt thereof.
2. A method for the treatment of an infectious bacterial disease which
comprises administering the erythromycin A compound or the
pharmaceutically acceptable salt thereof according to claim 1 to a patient
in an amount effective for said treatment.
Description
TECHNICAL FIELD
The present invention relates to antibiotic erythromycin A derivatives.
BACKGROUND ART
Erythromycin A is an antibiotic widely used as an agent for treating
infectious diseases caused by Gram-positive bacteria, mycoplasmas, etc.
However, erythromycin is decomposed by gastric acid due to its instability
to acids, and thus has a drawback of no constancy of movement in the body.
Hitherto many erythromycin derivatives have been prepared for the purpose
of the improvement of such biological or pharmacological properties. For
example, it is reported that 6-O-methylerythromycin A derivatives have an
improved stability to acids and have a superior in vivo antibacterial
activity in comparison with erythromycin A when administered orally (U.S.
Pat. No. 433,803). There are also recent reports relating to 11,12-cyclic
carbamate derivatives of erythromycin with the aim of expansion of
antibacterial spectrum as well as a stability to acids (EP. patent No.
487411, U.S. Pat. No. 4742049, EP. patent No. 676409 and EP. patent No.
638584), and further reports relating to erythromycin derivatives wherein
an acyl group has been introduced at the 3-position (EP. Patent No.
619320).
An object of the present invention is to provide novel antibiotics having a
strong antibacterial activity not only against previous
erythromycin-sensitive bacteria but also against Haemophilus influenzae
and erythromycin-resistant bacteria which recently show a tendency to
increase.
DISCLOSURE OF THE INVENTION
As a result of various researches on the antibacterial activity of
erythromycin derivatives, the present inventors have found that, among the
11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A, the
compounds containing a certain type of acyl group introduced at the
3-position have a strong antibacterial activity not only against previous
erythromycin-sensitive bacteria but also against Haemophilus influenzae
and certain erythromycin-resistant bacteria, thereby the present invention
has been accomplished.
The present invention relates to an erythromycin derivative represented by
Formula (I):
##STR2##
wherein R is a pyridyl group, a quinolyl group, a nitrophenyl group or a
methoxyphenyl group; or a pharmaceutically acceptable salt thereof.
In the present invention, the pharmaceutically acceptable salt refers to a
salt used in chemotherapy or prophylaxis of bacterially infectious
diseases. It includes, for example, a salt with an acid such as acetic
acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid,
maleic acid, tartaric acid, citric acid, stearic acid, succinic acid,
ethylsuccinic acid, lactobionic acid, gluconic acid, glucoheptonic acid,
benzoic acid, methanesulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic
acid, laurylsulfuric acid, malic acid, aspartic acid, glutaminic acid,
adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic
acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid,
oxalic acid, picric acid, thiocyanic acid, undecanic acid, polyacrylate
and carboxyvinyl polymer.
The compounds of the present invention can be prepared, for example, as
follows.
##STR3##
Step (1);
10,11-Anhydro-2',4"-di-O-acetyl-12--imidazolylcarbonyl-6-O-methylerythromy
cin A described in EP patent No. 638584 is reacted with hydrazine or
ydrazine monohydrate in an inert solvent at a temperature of from -30 to
100.degree. C., preferably from 0.degree. C. to room temperature, to give
an 11,12-cyclic carbamate compound, which is then reacted in a lower
alcohol or an aqueous lower alcohol (if desired, a base such as sodium
bicarbonate may be added herein) at a temperature of from 0 to 100.degree.
C for removal of the protective group at the 2'-position, thereby there is
obtained a compound represented by Formula (a). Examples of the inert
solvent to be used herein are acetonitrile, tetrahydrofuran,
N,N-dimethylformamide, dioxane, ethyl acetate, N-methylpyrrolidone, an
aqueous solvent thereof and a mixture thereof. Examples of the lower
alcohol used herein are methanol, ethanol and propyl alcohol.
Step (2); To Compound (a) is added benzyl chloroformate in an inert solvent
in the presence of sodium bicarbonate under ice-cooling, followed by
reacting them at a temperature of from 0 to 100.degree. C., preferably
from room temperature to 60.degree. C., to give a bis-benzyloxycarbonyl
compound, which is then reacted with an acid such as hydrochloric acid (if
desired, a mixture of a lower alcohol and the acid may be used herein) for
removal of the sugar at the 3-position, thereby there is obtained a
compound represented by Formula (b). The inert solvent and the lower
alcohol to be used herein are the same as in Step (1).
Step (3); Compound (b) is reacted using a reagent represented by the
formula:
R--CH.sub.2 COOH
(wherein R is as defined above) and an activating agent thereof in an inert
solvent in the presence of a base such as triethylamine or
4-dimethylaminopyridine at a temperature of -30 to 30.degree. C. to give a
compound represented by Formula (c). Examples of the activating agent to
be used herein are 1,3-dicyclohexylcarbodiimide,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and pivaloyl
chloride, and examples of the inert solvent to be used herein are
dichloromethane, dichloroethane, acetone, pyridine, ethyl acetate and
tetrahydrofuran.
Step (4); Compound (c) is subjected to hydrogenolysis in an ordinary manner
to give a compound represented by Formula (d) (wherein R is as defined
above).
Step (5); Compound (d) is reacted in an inert solvent in the presence of an
acid such as acetic acid using 3-(4-quinolyl)propanal and a reducing agent
to give a compound of the present invention represented by Formula (e)
(wherein R is as defined above). Examples of the inert solvent to be used
herein are methanol, ethanol and dichloromethane, and examples of the
reducing agent to be used herein are sodium borohydride, sodium
cyanoborohydride and sodium triacetoxyborohydride.
The erythromycin A derivatives of the present invention can be administered
orally or parenterally. It can be administered in a dosage form such as
tablets, capsules, powders, troches, ointments, suspensions, suppositories
or injectional preparations, all of which can be prepared by conventional
preparation techniques. The dose is from 50 to 1,000 mg per day for the
treatment of adults, and it can be administered in 2 or 3 portions. This
dose can be properly increased or decreased depending on the age, body
weight and conditions of the patient.
MODE FOR CARRYING OUT THE INVENTION
The present invention is illustrated in more detail by the following
examples and experiment.
EXAMPLE 1
Preparation of
11-deoxy-11-{2-(3-(4-quinolyl)propyl)hydrazino}-3-O-(3-pyridyl)acetyl-5-O-
desosaminyl-6-O-methylerythronolide A 11,12-cyclic carbamate
(1) In 50 ml of acetonitrile was dissolved 5.45 g (6.0 mmol) of 10,
11-anhydro-2',4"-di-O-acetyl-12-O-imidazolylcarbonyl-6-O-methylerythromyci
n A described in EP patent No. 638584, and then 1.50 ml (30.0 mmol) of
hydrazine monohydrate was added thereto at room temperature, followed by
stirring overnight. The reaction solution was evaporated under reduced
pressure, and the residue was dissolved in 50 ml of methanol and refluxed
under heating for 4 hours. After evaporation of the solvent, the residue
was dissolved in 60 ml of tetrahydrofuran, and then 3.0 g (36.0 mmol) of
sodium bicarbonate and 2.6 ml (18 mmol) of benzyl chloroformate were added
thereto, followed by stirring under ice-cooling. The reaction temperature
was raised to 50.degree. C., followed by stirring overnight. The reaction
solution was made basic by addition of 4N sodium hydroxide and extracted
with chloroform. The organic layer was dried over anhydrous magnesium
sulfate, and the solvent was evaporated under reduced pressure. The
residue was dissolved in ethanol, and after addition of 2N hydrochloric
acid, stirred at 60.degree. C. for 8 hours. After the reaction, the
reaction solution was made basic by addition of 4N aqueous sodium
hydroxide solution, and extracted with chloroform. The organic layer was
dried over anhydrous magnesium sulfate, and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel column
chromatography (hexane acetone:triethylamine=10:3:0.3) to give 3.4 g of
2'-O-benzyloxycarbonyl-11-(2-(N-benzyloxycarbonyl)hydrazino)-5-O-desosamin
yl-6-O-methylerythronolide A 11,12-cyclic carbamate.
(2) In 15 ml of dichloromethane were dissolved 1.74 g (10.0 mmol) of
3-pyridylacetic acid hydrochloride, 1.86 ml (13.3 mmol) of triethylamine
and 1.24 ml (10.1 mmol) of pivaloyl chloride, followed by stirring at
-15.degree. C. for 20 minutes. To the solution was added a solution of 3 g
(3.34 mmol) of the compound obtained in the above (1) in 15 ml of
dichloromethane, and after stirring for 10 minutes, 409 mg (3.35 mmol) of
4-dimethylaminopyridine was added thereto, and then stirring was further
continued for 1.5 hours. The reaction solution was concentrated under
reduced pressure and extracted with ethyl acetate. The organic layer was
washed with water and a saturated aqueous sodium chloride solution
successively, and dried over anhydrous magnesium sulfate, and the solvent
was evaporated under reduced pressure. The residue was purified by silica
gel column chromatography (hexane:acetone:triethylamine=10:6:0.2) to give
2.59 g of the 3-O-pyridylacetyl compound.
(3) In 15 ml of methanol was dissolved 2.3 g (2.26 mmol) of the compound
obtained in the above (2), and then 0.46 g of 10% palladium carbon and
1.43 g (22.7 mmol) of ammonium formate were added thereto, followed by
stirring at room temperature for 4 hours. After removal of the catalyst by
filtration, the filtrate was concentrated under reduced pressure and
worked up in the same manner as in the above (2) using chloroform as an
extract solvent. After evaporation of the solvent, the residue was
purified by silica gel column chromatography (chloroform:methanol:aqueous
ammonia=20:1:0.1) to give 1.39 g of the 11-hydrazino-11,12-cyclic
carbamate compound.
(4) In 10 ml of methanol was dissolved 0.10 g (0.13 mmol) of the compound
obtained in the above (3), and then 53 mg (0.26 mmol) of
3-(4-quinolyl)propanal (of which preparation method was shown in Reference
Example 1) and 61 .mu.l (1.1 mmol) of acetic acid were added thereto.
Thereafter, 33.4 mg (0.53 mmol) of sodium cyanoborohydride was added to
the resulting solution under ice-cooling, the temperature thereof was
returned to room temperature, followed by stirring overnight. The reaction
solution was made basic by addition of 4N sodium hydroxide and extracted
with diethyl ether. The organic layer was dried over anhydrous magnesium
sulfate, and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
(chloroform:methanol:aqueous ammonia=10:1:0.1) to give 0.10 g of the title
compound.
REFERENCE EXAMPLE 1
Preparation of 3-(4-quinolyl)propanal to be used in Example 1 (4)
(1) In 100 ml of methanol was dissolved 7.92 g (50.4 mmol) of
4-quinolinecarboxaldehyde, and then 8.9 ml (55.4 mmol) of
trimethylphosphonoacetate (MeO).sub.2 P(O)CH.sub.2 CO.sub.2 Me and 13.9 g
(101 mmol) of potassium carbonate were added thereto, followed by stirring
at room temperature for 2 hours. The reaction solution was diluted with
diethyl ether and then washed with water. The organic layer was dried over
anhydrous magnesium sulfate, and the solvent was evaporated under reduced
pressure. The residue was dissolved in 100 ml of methanol, and after
addition of 4.0 g of 5% palladium carbon, stirred under a hydrogen gas
stream for 2 hours. The palladium carbon was filtered through Celite, and
the solvent was evaporated under reduced pressure to give 10.7 g of the
ester compound. (2) In 250 ml of anhydrous diethyl ether was dissolved
10.7 g (49.7 mmol) of the ester compound obtained in the above (1), and
then 3.77 g (99.4 mmol) of lithium aluminum hydride was added thereto
under ice-cooling, followed by stirring for an hour. 3.8 Milliliters of
water and 3.8 ml of 4N sodium hydroxide then an additional 11.6 ml of
water were added to the solution, followed by stirring for an hour. The
precipitate was removed by filtration, and the solvent was evaporated
under reduced pressure to give 6.9 g of the alcohol compound.
(3) In 5.0 ml of dichloromethane was dissolved 0.43 ml (6.0 mmol) of
dimethyl sulfoxide, followed by stirring at -60.degree. C. To the
resulting solution was dropwise added a solution of 0.26 ml (3.0 mmol) of
oxalyl chloride in 5 ml of dichloromethane and stirred for 10 minutes. To
the solution was then added dropwise a solution of 0.30 g (1.50 mmol) of
the alcohol compound obtained in the above (2) in 5.0 ml of
dichloromethane. 1.66 Milliliters (12.0 mmol) of triethylamine was added
thereto, followed by stirring for 10 minutes. After the reaction, the
reaction solution was washed with distilled water and then with an aqueous
sodium chloride solution. The organic layer was dried over anhydrous
magnesium sulfate, and the solvent was evaporated under reduced pressure
to give 0.30 g of 3-(4-quinolyl)propanal. Experiment [In Vitro
Antibacterial Activity]
The in vitro antibacterial activity of the compound obtained in Example 1
as an example of the compound of the present invention against various
experimental bacteria was measured using sensitive disc media (produced by
Eiken Chemical Co.) according to the MIC measuring method specified by the
Japan Society of Chemotherapy. Erythromycin A was used as a comparative
drug. The results are expressed as MIC value (Minimum Inhibitory
Concentration against microorganism, .mu.g/ml), and shown in Table 1. The
compound obtained in Example 1 was indicated to have a strong
antibacterial activity not only against erythromycin-sensitive bacteria
but also against Haemophilus influenzae and certain erythromycin-
resistant bacteria.
TABLE 1
______________________________________
Comparative
Compound of
Microorganism/Compound drug Example 1
______________________________________
S. aureus 209P-JC
0.20 0.10
S. aureus B1 >100 0.10
S. pneumoniae IID553 0.10 0.20
S. pneumoniae BM210 0.78 0.20
S. pneumoniae BM205 >100 0.39
H. influenzae ATCC 19418 6.25 3.13
______________________________________
Industrial Applicability
The compounds of the present invention have a strong antibacterial activity
not only against erythromycin-sensitive bacteria but also against certain
erythromycin-resistant bacteria and Haemophilus influenzae. Accordingly,
the compounds of the present invention are useful as antibacterial agents
for the treatment of bacterially infectious diseases in human beings and
animals (including farm animals).
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